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Pharmacologyofefferentnervoussystem
Shi-HongZhang(张世红NervousSystemPeripheralNervousSystem(PNS)CentralNervousSystem(CNS)OrganizationofthenervoussystemSympatheticPeripheralNervousSystem(PNS)EfferentDivisionAfferentDivisionAutonomicSystem(ANS)SomaticSystemParasympatheticEntericTheEntericNervousSystem(+SNS/PSNS)Sympatheticstimulationcauses:stimulatesheartbeatraisesbloodpressuredilatesthepupilsdilatesthetracheaandbronchistimulatestheconversionofliverglycogenintoglucoseshuntsbloodawayfromtheskinandvisceratotheskeletalmuscles,brain,andheartinhibitsperistalsis〔蠕动〕inthegastrointestinal(GI)tractinhibitscontractionofthebladderandrectumParasympatheticstimulationcauses:slowingdownoftheheartbeatloweringofbloodpressureconstrictionofthepupilsincreasedbloodflowtotheskinandvisceraperistalsisoftheGItractOrganizationofthenervoussystemSympatheticNervousSystemPeripheralNervousSystem(PNS)CentralNervousSystem(CNS)EfferentDivisionAfferentDivisionAutonomicSystem(ANS)SomaticSystemParasympatheticEntericDrugsthatproducetheirprimarytherapeuticeffectbymimickingoralteringthefunctionsofautonomicnervoussystemarecalledautonomicdrugs.NeurotransmittersSynthesisStorageReleaseDegradationReceptorsActivationBlockadeDrugactionsandclassification(1)Mimetics
-direct-acting:receptoragonists
-
indirect-acting:increasingamountsand/oreffectsoftransmitters(2)Antagonists
-
direct-acting:receptorantagonists
-
indirect-acting:decreasingamountsand/oreffectsoftransmittersCholinergicPharmacologyAdrenergicPharmacologyAutonomicPharmacologyCASESTUDYInmid-afternoon,acoworkerbrings43-year-oldJMtotheemergencydepartmentbecauseheisunabletocontinuepickingvegetables.Hisgaitisunsteadyandhewalkswithsupportfromhiscolleague.JMhasdifficultyspeakingandswallowing,hisvisionisblurred,andhiseyesarefilledwithtears.HiscoworkernotesthatJMwasworkinginafieldthathadbeensprayedearlyinthemorningwithamaterialthathadtheodorofsulfur.Within3hoursafterstartinghiswork,JMcomplainedoftightnessinhischestthatmadebreathingdifficult,andhecalledforhelpbeforebecomingdisoriented.CholineUptake→AChSynthesisCholine+AcCoA→ACh
ChATAChStorageAChReleaseAChEffects-Postsynaptic-PresynapticAChinactivationACh
→Choline+Acetate
AChECholinergicTerminalRegulation-byautoreceptorsAChactingonpresynapticm2-cholinergicreceptors-byheteroreceptorsNEactingonpresynapticalpha2-adrenergicreceptors
-bymetabolism(extraneuronal)AcetylcholineReleaseAChinactivation
CholinesterasesAcetylcholinesterase
islocatedatcholinergicsynapsesandinerythrocytes(doesnothydrolyzesuccinylcholine)
Pseudocholinesterase
(synonyms:plasmacholinesteraseorbutyrylcholinesterase丁酰胆碱脂酶
)occursmainlyinplasma,liverandinglia(hydrolyzessuccinylcholine)CholinergicReceptors
Muscarinicreceptors(Mreceptors)
M1,3,5(smoothmuscles);M2,4(heart)
G-proteinCoupledEndOrgansNicotinicreceptors(Nreceptors)
NN(N1)receptors;NM(N2)
receptorsLigand-gatedIonChannelsNMJ&GangliaMreceptors:G-proteinCoupled
Muscarinic
Receptor
Signaling
PathwaysDepressionoftheheart
(heartrate,conduction)Contractionofsmoothmuscles
(sensitive:GItract,bronchial,urinarybladder;insensitive:uterine,bloodvascular)Exocrineglands
(sensitive:sweat,tear,salivary;insensitive:GItract);Eye
(contractionofsphinctermuscleofiris:miosis;contractionofciliarymuscle睫状肌:contractionfornearvision)Mreceptors:CholinergicVasodilationTheresponseofanisolatedbloodvesseltoAChdependsonwhethertheendotheliumisintact(unrubbed)ormissingWhentheendotheliumispresent,AChcausessmoothmusclerelaxationbystimulatingtheproductionofnitricoxide(NO)intheendotheliumIntheabsenceoftheendothelium,asmallamountofvasoconstrictionisobservedNNreceptors〔N1receptors〕-Sympatheticandparasympatheticganglia-AdrenalmedullaNMreceptors〔N2receptors〕-TheNeuromuscularJunction(NMJ)(Contractionofskeletalmuscles)NreceptorsAttheNMJ,Nreceptors
pentamericwithfourtypesofsubunits,twoasubunitsbindAChforligandgatingAllothernAChRs,includingthoseattheperipheralganglia,have2a’sand3b’sNreceptors:Ligand-gatedIonChannelsGanglionicNeurotransmissionN=NicotinicAChRM=MuscarinicAChREPSP=ExcitatoryPostsynapticPotentialIPSP=InhibitoryPostsynapticPotentialABTheNeuromuscularJunction(NMJ)MyastheniaGravisThismeans“seriousdisordertheNMJ〞ThisisanautoimmunediseaseAntibodiesagainsttheasubunitofthenAChRTheabilityofAChtoactivatethenAChRsisblockedbytheantibodiesAsmanyautoimmunediseases,stresscanmakethesymptomsworseTreatmentistopotentiatecholinergicsignalingandtoremovetheantibodies(blooddialysis)1.Cholinomimetics(1)Direct-actingdrugs:CholinoceptoragonistsM,Nreceptoragonists:
acetylcholineMreceptoragonists:
pilocarpineNreceptoragonists:
nicotine(2)Indirect-actingdrugs:Cholinesteraseinhibitors(Anticholinesterases)Reversible:
neostigmine新斯的明Irreversible:
organophosphates有机磷酸酯类
Cholinesterasereactivators:pralidoximeiodide
碘解磷定Drugclassification2Cholinergicantagonists(1)CholinoceptorantagonistsMcholinoceptorantagonists
atropine(Antimuscarinicdrugs)Ncholinoceptorantagonists
NNcholinoceptorantagonists:
mecamylamine
(Ganglionicblockingdrugs,rarelyused)
NMcholinoceptorantagonists:succinylcholine
(Neuromuscularblockingdrugs)(2)BotulinumToxin
(Botox,blocksAChrelease)
DrugclassificationCholinomimeticsAchderivatives〔胆碱酯类〕Naturalmuscarinicagonists(生物碱类M受体冲动剂)Nicotinicreceptoragonists(N受体冲动剂)Direct-actingdrugsAChEresistantBondcleavedbyAChE醋甲胆碱氯贝胆碱卡巴胆碱乙酰胆碱AChDerivativesAChDerivativesBethanechol
氯贝胆碱ismostcommonlyused,particularlypost-opforthetreatmentofparalyticileusandurinaryretentionNaturalMuscarinicAgonistsNicotinicpotencyArecoline:arecaorbetalnuts(India,E.Indies)Pilocarpine:pilocarpus(S.Amer.shrub)Muscarine:amanitamuscaria(mushroom)槟榔碱毛果芸香碱毒蕈碱Poisoningcausesmuscarinicoverstimulation: -salivation,lacrimation,visualdisturbances; -abdominalcolicanddiarrhea -bronchospasmandbradycardia -hypotension;shockTreatmentiswithatropineAtropabelladonnaAmanitamuscaria“Food〞Poisoning颠茄伞形毒蕈Eyes
Miosis(缩瞳):contractionofsphinctermuscleofirisLowingintraocularpressure:enlargingangleofanteriorchamber,increasingdrainageofaqueoushumorSpasmofaccommodation(调节痉挛):contractionofciliarymuscle,contractionfornearvision
Ophthalmological眼科uses
Glaucoma青光眼:
narrow(closed)-or
wide(open)-anglesusedfortheemergencyloweringofintraocularpressure
Iritis:
miotics缩瞳药/mydriatics扩瞳药PilocarpinepilocarpineatropinelensmiosismydriasisparalysisofaccommodationnearsightspasmofaccommodationfarsightirisCiliarymuscle(contraction)AnteriorchamberzonulezonulePosteriorchamberAnteriorchamberCiliarymuscle(dilation)CanalofSchlemmCirculationofaqueoushumor
GlaucomaOpen-angleglaucoma:diseaseoftheagingeye-increasedintraocularpressure,degenerationoftheoptichead,andrestrictedvisualfieldObstructionoftheaqueousdrainageleadstoelevatedintraocularpressure(IOP),andmayresultinglaucomatousdamagetotheopticnerveGlaucomaGlaucomamanagementinvolvesloweringIOPby -Decreasingaqueousproductionbytheciliarybody -IncreasingaqueousoutflowthroughthetrabecularmeshworkanduvealoutflowpathsPilocarpine:increaseaqueousoutflowbycontractionoftheciliarymuscletoincreasetoneandalignmentofthetrabecularnetwork
〔2〕Promotingsecretionofexocrineglands,especiallyinsweat,salivaryandtearglandsSystemicuseAntidote解毒剂foratropinepoisoningAdverseeffectsM-likesyndromePilocarpineActionsatganglia,NMJ,brainarecomplexandfrequentlyunpredictable,becauseofthevarietyofneuroeffectorsitesandbecausenicotinebothstimulatesanddesensitizeseffectors.
Periphery:
HR,BP,GItone&motility
CNS:
stimulation,tremors,respiration,emeticeffectsTheaddictivepowerofcigarettesisdirectlyrelatedtotheirnicotinecontent.Nreceptoragonists:Nicotine1.Cholinomimetics(1)Direct-actingdrugs:CholinoceptoragonistsM,Nreceptoragonists:acetylcholineMreceptoragonists:pilocarpineNreceptoragonists:nicotine(2)Indirect-actingdrugs:Cholinesteraseinhibitors(Anticholinesterases)Reversible:
neostigmine新斯的明Irreversible:
organophosphates有机磷酸酯类
Cholinesterasereactivators:pralidoximeiodide
碘解磷定DrugclassificationAcetylcholinesterase(AChE)ActivityA.Competitive(reversible)B.Carbamates(氨甲酰类slowlyreversible)C.Organophosphates(irreversible)AChEInhibitorsneostigmineTheseagentsarereversibleandareusedmedically(glaucomaorMG)Theseagentsareirreversibleandareusedaspesticidesorforglaucoma毒扁豆碱新斯的明依酚氯铵AcetylcholinesteraseInhibitors:
ReversibleEdrophonium(依酚氯铵)Rapidlyabsorbed;Ashortdurationofaction(5-15min);Competitive(reversible)Usedindiagnosisofmyastheniagravis.Excessdrugmayprovokeacholinergiccrisis,atropineistheantidote.OtherreversibleACHEI:tacrine他克林,donepezil多奈哌齐AcetylcholinesteraseInhibitors:
Carbamates
InhibitoryEffectsareslowlyreversibleRepresentativeDrugsneostigmine(quaternaryamine季铵)pyridostigmine(quaternaryamine)physiostigmine(tertiaryamine叔胺)
quaternaryamineseffectiveinperipheryonlytertiaryamineseffectiveinperipheryandCNS〔fat-soluble〕Pharmacologicaleffects
AChE(-),AChrelease↑,stimulatingNMRstrongereffectonskeletalmuscleseffectiveonGItractandurinarybladdermorepolarandcannotenterCNSrelativelyineffectiveonCVS,glands,eyeNeostigmine新斯的明ClinicalusesMyastheniagravis:symptomatictreatmentoverdose:cholinergiccrisis胆碱能危象:大量出汗,大小便失禁,瞳孔缩小,睫状肌痉挛,心动过缓,低血压,肌无力,呼吸困难Paralyticileus麻痹性肠梗阻urinaryretention:postoperativeabdominaldistensionandurinaryretentionParoxysmalsuperventriculartachycardia〔rarelyuse〕Antidotefortubocurarine(筒箭毒碱)andrelateddrugpoisoningGlaucomaNeostigmineAdverseeffectsCholinergiceffects:muscarinicandnicotiniceffects,treatedwithatropine(muscarinic)Contraindications:mechanicalileus〔机械性肠梗阻〕urinaryobstructionbronchialasthmapoisoningofdepolarizingskeletalmusclerelaxants(e.g.succinylcholine,琥珀酰胆碱)NeostigmineAcetylcholinesteraseInhibitors:IrreversibleBondishydrolyzedinbindingtotheenzymeForophthalmicuse乙磷硫胆碱梭曼对硫磷对氧磷马拉硫磷马拉氧磷Dichlorvos敌敌畏Dimethoate乐果(1)ToxicsymptomsAcuteintoxicationMuscarinicsymptom:
eye,exocrineglands,respiration,GItract,urinarytract,CVSNicotinicsymptoms:
NN:elevationofBP,increaseofHR;
NM:tremorofskeletalmusclesCNSsymptoms:excitation,convulsion;depression(advancedphase)OrganophosphatesCASESTUDYInmid-afternoon,acoworkerbrings43-year-oldJMtotheemergencydepartmentbecauseheisunabletocontinuepickingvegetables.Hisgaitisunsteadyandhewalkswithsupportfromhiscolleague.JMhasdifficultyspeakingandswallowing,hisvisionisblurred,andhiseyesarefilledwithtears.HiscoworkernotesthatJMwasworkinginafieldthathadbeensprayedearlyinthemorningwithamaterialthathadtheodorofsulfur.Within3hoursafterstartinghiswork,JMcomplainedoftightnessinhischestthatmadebreathingdifficult,andhecalledforhelpbeforebecomingdisoriented.(1)ToxicsymptomsChronicintoxicationusuallyoccupationalpoisoningplasmaChEactivity↓,weakness,restlessness,anxiety,tremor,miosis,……Organophosphates(2)DetoxicationEliminationofpoison;SupportivetherapyAntidotesAtropine-antagonizingmuscariniceffects;early,largedose,andrepeateduseCholinesterasereactivators-reactivationofphosphatedAChE;moderate-severepatients,earlyuse(Moreeffectiveontremor),combinedwithatropinePyraloximemethoiodide(PAM,碘解磷定)Pralidoximechloride〔氯解磷定〕:saferthanPAMObidoximechloride〔双复磷〕:twoactiveoximegroupsOrganophosphatesOrganophosphatesPralidoxime〔解磷定〕canrestoreAChEactivityifadministeredsoonaftertoxinexposure.Conjugatingwithorganophosphatebyoximegroup;Conjugatingwithfreeorganophasphates
Whyisn’tthisACHEIpesticideneurotoxictohumans?Insectsandmammalsmetabolizethe‘prodrug’differentlyMammals–esteraseactivity:hydrolyzesthemoleculeintoinactivemetabolitesInsects-P450metabolism:P-SbondconvertedtoP-Obond:now,themolecule,malaoxon,isanactiveinhibitorMalathion马拉硫磷
glaucoma(e.g.physiostigmine毒扁豆碱,echothiophate乙磷硫胆碱
)myastheniagravis(e.g.Edrophonium,neostigmine,pyridostigmine)reverseneuromuscularblockadefromcompetitiveantagonists(neostigmine)Alzheimer’sdisease(tacrine&donepezil,galanthamine)chemicalwarfareagentsinsecticidesSummary:ACHEIApplicationsPharmacologicalActions:IncreasesAChconcentrationsatcholinergicsynapses,therebyincreasingcholinergicactivity.2Cholinergicantagonists(1)CholinoceptorantagonistsMcholinoceptorantagonists
atropine(Antimuscarinicdrugs)Ncholinoceptorantagonists
NNcholinoceptorantagonists:
mecamylamine
(Ganglionicblockingdrugs,rarelyused)
NMcholinoceptorantagonists:succinylcholine
(Neuromuscularblockingdrugs)BotulinumToxin(botox,blocksAChrelease)
DrugclassificationMuscarinicAntagonists
(Antimuscarinicdrugs)Tertiaryamines〔叔铵〕Quaternaryamines〔季铵〕异丙托铵噻托溴铵东莨菪碱Atropabelladonna颠茄Daturastramonium曼陀罗Daturasp.洋金花山莨菪HenbaneSeed1.PharmacologicaleffectsAtropine(1)Inhibitionofexocrineglandsecretionsalivary,sweatglandstear,respiratorytractglandsrelativelyineffective:GItract(2)Eye
mydriasis瞳孔散大riseinintraocularpressureparalysisofaccommodation调节麻痹pilocarpineatropinelensmiosismydriasisparalysisofaccommodationnearsightspasmofaccommodationfarsightirisCiliarymuscle(contraction)AnteriorchamberzonulezonulePosteriorchamberAnteriorchamberCiliarymuscle(dilation)CanalofSchlemm1.Pharmacologicaleffects(3)
Antispasmodicactiononsmoothmuscle
sensitive:GI,urinarybladder(spasmodicstate)relativelyinsensitive:bileduct,urinarytract,bronchialtractinsensitive:uterusAtropinePharmacologicaleffects(4)Cardiovascularsystem:dosedependent
Lowertherapeuticdoses:HR↓(bradycardia);
Bloodvesselsandbloodpressure:
noeffectModeratetohightherapeuticdoses/highvagaltone:HR↑(tachycardia);A-Vconduction↑Largerdoses:cutaneousvasodilatation(5)CNSstimulation:sedation,memoryloss,psychosis
(highdose)Atropine2.Clinicaluses(1)OphthalmologyMeasurementoftherefractiveerrors(屈光不正):childrenAcuteiritisoriridocyclitis:mydriatics/miotics(2)AntispasmodicagentGI,biliaryorrenalcolic,enuresis(3)Inhibitingexocrineglandsecretion
Preanestheticmedication麻醉前用药(4)Bradycardiasinusornodalbradycardia,A-Vblock(5)Antidotefororganophosphatepoisoning(6)Septicshock感染性休克Atropine3.Adverseeffects(1)Sideeffectsdrymouth,blurredvision,“sandyeyes〞(2)toxicityLethaldose:80~130mg(adult),10mg(child)Low:xerostomia(drymouth);anhidrosis(dryskin),tachycardiaModerate:aboveplusmydriasis,cycloplegia(睫状肌麻痹);difficultyspeaking,swallowing&urinating;andhot,red,dryskinHigh:aboveplusataxia,hallucinations幻觉&delirium谵妄;comaAtropine3.Adverseeffects(3)DetoxicationSupportivetreatmentSymptomatictreatment:e.g.diazepamforCNSsymptoms.Antidote:Physostigmineorpilocarpine(4)Contraindicationsglaucoma,prostatauxe前列腺肥大,feverAtropineActionsandclinicalusesPeripheraleffectsaresimilartoatropine;buthasstrongercentraleffects(depression)Pre-anestheticmedication,preventionofmotionsickness,Parkinson’sdisease
Scopolamine东莨菪碱Anisodamine(654-1,2)ActionsandclinicalusesPeripheraleffects,similartoatropine;lowertoxicitySepticshockandvisceralcolic(relievespasmofvascularsmoothmuscles)Tropicamide托吡卡胺:mydriatic,cycloplegicshorterduration(1/4day)Propantheline丙胺太林,普鲁本辛poorabsorption(po)andBBBpenetrationantispasmodiceffectsinGI,treatmentofpepticulcerIpratropium异丙托铵:asthmaBenztropine苯托品:Parkinson’sdiseaseTrihexyphenidyl苯海索Pirenzepine哌仑西平:M1selective,pepticulcer,asthmaSynthesizedsurrogatesCASESTUDYJH,a63-year-oldarchitect,complainsofurinarysymptomstohisfamilyphysician.Hehashypertensionandthelast8years,hehasbeenadequatelymanagedwithathiazidediureticandanangiotensin-convertingenzymeinhibitor.Duringthesameperiod,JHdevelopedthesignsofbenignprostatichypertrophy,whicheventuallyrequiredprostatectomytorelievesymptoms.Henowcomplainsthathehasanincreasedurgetourinateaswellasurinaryfrequency,andthishasdisruptedthepatternofhisdailylife.WhatdoyoususpectisthecauseofJH’sproblem?Whatinformationwouldyougathertoconfirmyourdiagnosis?Whattreatmentstepswouldyouinitiate?NicotinicreceptorantagonistsActingonsympatheticandparasympatheticganglioniccells;reducingbloodpressurebyinhibitingsympatheticganglia(havebeenabandonedforclinicaluse,duetotheirlackofselectivity)Short-acting;tachyphylaxis(快速抗药反响)UsedfortreatmentofhypertensionTrimethaphan(咪噻芬)Mecamylamine(美加明)NNreceptorantagonists
(Ganglionicblockingdrugs)Twoclasses:Depolarizing:succinylcholine琥珀酰胆碱Non-depolarizing:drugsactascompetitiveantagonists
d-tubocurarine筒箭毒碱Note:BelongtoSkeletalMuscleRelaxants.Itisimportanttorealizethatmusclerelaxationdoesnotensureunconsciousness,amnesia,oranalgesia.NMreceptorantagonists(Neuromuscularblockingdrugs
)1.Depolarizingneuromuscularblockers(Non-competitive)(depolarizingskeletalmusclerelaxants)actasacetylcholine(ACh)receptoragoniststhedepolarizedmembranesremaindepolarizedandunresponsivetosubsequentimpulses(ie,theyareinastateofdepolarizingblock).notmetabolizedbyAChE-diffuseawayfromtheneuromuscularjunctionandarehydrolyzedintheplasmaandliverbypseudocholinesterase(nonspecificcholinesterase,plasmacholinesterase,orbutyrylcholinesterase)andeliminationbykidneyNMreceptorantagonists(Neuromuscularblockingdrugs
)Succinylcholine(Scoline司可林)Succinylcholineistheonlydepolarizingagentusedclinically(t1/2=2-4min).Propertiesofactions:initiallytransientfasciculations〔肌束震颤〕anti-AChEpotentiatestheireffectstachyphylaxisafterrepeatedusesnoganglion-blockingeffectsattherapeuticdosesthedrugsarehighlypolar,poorbioavailability;i.v.asquaternarycompounds,donotenterCNSacetylcholinesuccinylcholineMainpharmacologicaleffectsTransientexcitation(fasciculations),andtheninhibition(relaxation)RelaxSkeletalMusclesin
neck,limbs>face,tongue,throat;lesseffectiveonbreathmusclesattherapeuticdosesSuccinylcholine(Scoline)ClinicalusesAnadjuvantinanesthesiaoroperationIntubationoftrachea,esophagus,etc.Preventionoftraumaduringelectroshocktherapy〔无抽搐电休克疗法〕Contraindicatedinawakepatients,shoulduseunderanesthesiaSuccinylcholine(Scoline)Adverseeffects(1)Apnea(respiratoryparalysis)
overdoseorhypersensitivepatients;
neostigminepotentiatesthetoxiceffects(2)Musclespasm
muscularpainafteroperationSuccinylcholine(Scoline)(3)ElevationofK+inplasma
contraindicatedinpatientswithatendencyofhyperkalemia(4)Malignanthyperthermia
geneticabnormality,treatedbydantrolene(Ca2+releaseinhibitor)(5)Others
riseinintraocularpressure(glaucoma);histaminereleaseSuccinylcholine(Scoline)GeneticVariation:EffectsonDurationofActionofSuccinylcholineDurationofactionisprolongedbyhighdosesorbyabnormalmetabolism.Thelattermayresultfrom
hypothermia(decreasestherateofhydrolysis),lowpseudocholinesteraselevels,orageneticallyaberrantenzyme.Lowpseudocholinesteraselevelsgenerallyproduceonlymodestprolongationofsuccinylcholine'sactions(2-20min).Onein50patientshasonenormalandoneabnormal(atypical)pseudocholinesterasegene,resultinginaslightlyprolongedblock(20-30min).Evenfewer(1in3000)patientshavetwoabnormalgenes(homozygousatypical)thatproduceanenzymewithlittleornoaffinityforsucci
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